Apoptosis in HepG2 cells exposed to high glucose

Chandrasekaran, Karthikeyan; Swaminathan, Kavitha; Chatterjee, Suvro; Dey, Aparajita

doi:10.1016/j.tiv.2009.10.020

Cited by 85 publications

(72 citation statements)

References 34 publications

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“…Similarly, Woodcroft et al reported that absence of insulin attenuated induction of phenobarbital induced CYP3A in hepatocytes (30). In terms of the contribution of glucose, we discovered that physiological or pathological levels of glucose (5.5, 25 mM) failed to affect the activity of CYP3A4 in HepG2 cells, while a much higher glucose level (68 mM) reduced CYP3A4 activity in HepG2 cells without affecting the cell viability (31), inferring that induction of CYP3A4 did not result from the increased level of glucose. Several studies have showed that consumption of glucose or high carbo hydrate diet decreased metabolism of some drugs such as barbiturates, antipyrine, and theophylline (32,33).…”

Section: Discussionsupporting

confidence: 62%

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Duan

et al. 2014

J Pharmacol Sci

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Abstract.Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contribut ing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concen trationdependently upregulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N4 cells. Data from western blotting and QTPCR showed that induction of CYP3A4 activity was associated with upregulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid-induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK, PKC, and NFkB-dependent pathways, whereas that by palmitic acid was possibly associated with the PKCdependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions.

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Section: Discussionsupporting

confidence: 62%

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Duan

et al. 2014

J Pharmacol Sci

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“…The Bcl-2 protein family, including anti-apoptotic and pro-apoptotic proteins, regulates cell death by modulating mitochondrial membrane permeability during apoptosis. Bcl-2 is anti-apoptotic, while Bax is an antagonist of Bcl-2, which inserts into the mitochondrial outer membrane, allows for the release of Cyt c and AIF, and subsequently activates caspase-dependent or independent apoptotic pathway [21]. In the present study, the involvement of mitochondrial pathway in 8-MOP-induced apoptosis is confirmed by observing changes in MMP, Bax/ Bcl-2 ratio and release of Cyt c and AIF (Fig.…”

Section: Discussionsupporting

confidence: 78%

8-Methoxypsoralen Induces Intrinsic Apoptosis in HepG2 Cells: Involvement of Reactive Oxygen Species Generation and ERK1/2 Pathway Inhibition

Yang

Xiong

Luo

et al. 2015

Cell Physiol Biochem

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Background/Aims: 8-Methoxypsoralen (8-MOP), a formerly considered photosensitizing agent, induces apoptosis when used alone. On this basis, the present study was designed to explore the effects and mechanisms of 8-MOP-induced apoptosis in human hepatocellular carcinoma HepG2 cells, independent of its photoactivation. Methods: We analyzed the cell viability with MTT assay. Flow cytometry was used to examine the apoptosis rate, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation after specific staining. The expression and location of apoptosis-associated protein as well as the activation status of cell signaling pathway were determined by Western blot analysis. Results: 8-MOP significantly decreased cell viability and induced cell apoptosis through mitochondrial apoptotic pathway, as demonstrated by increased Bax/Bcl-2 ratio, collapsed MMP, and induced cytochrome c release (Cyt c) and apoptosis-inducing factor (AIF) transposition. ROS generation was significantly increased by 8-MOP and the eradication of ROS significantly abolished 8-MOP-induced apoptosis. In addition, the activation of ERK1/2 was drastically decreased by 8-MOP as ERK inhibitor PD98059, indicating a role of ERK1/2 signaling pathway in 8-MOP-induced cell apoptosis. Conclusion: 8-MOP induces intrinsic apoptosis by increasing ROS generation and inhibiting ERK1/2 pathway in HepG2 cells. The findings are important in substantiating the anti-tumor role of 8-MOP in cancer therapy.

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“…Previous studies in HepG2 cells demonstrated that ROS generation is increased in cells cultured in 30 mmol/l glucose for 48 h, but with no changes in cell viability until 7 days (Palmeira et al 2007). It was reported that HepG2 cells cultured in 50 mmol/l glucose for 72 h showed a significant increase in apoptosis, accompanied by an increase in ROS levels (Chandrasekaran et al 2010). Different cell models adopted or the shorter incubation period or the lower glucose concentration could possibly explain the discrepancy in these studies.…”

Section: Discussionmentioning

confidence: 93%

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening

Yin¹,

Zheng²,

Pan³

et al. 2015

Journal of Molecular Endocrinology

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Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro, in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 mmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction.

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Apoptosis in HepG2 cells exposed to high glucose

Cited by 85 publications

References 34 publications

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

Increased Levels of Fatty Acids Contributed to Induction of Hepatic CYP3A4 Activity Induced by Diabetes — In Vitro Evidence From HepG2 Cell and Fa2N-4 Cell Lines

8-Methoxypsoralen Induces Intrinsic Apoptosis in HepG2 Cells: Involvement of Reactive Oxygen Species Generation and ERK1/2 Pathway Inhibition

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening

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